This invention relates to the fields of pharmaceutical and organic chemistry, and provides novel intermediates which are useful in the synthesis of 5,6-dihydropyrrolo[2,3-d]pyrimidine antimetabolites of the antifolate type. This invention also relates to processes for the preparation of such intermediates.
Substituted pyrrolo[2,3-d]pyrimidine-based antifolates have been used for a number of years as chemotherapeutic agents in the treatment of cancer. One such drug, methotrexate, is now one of the most widely used anticancer drugs; and many other compounds in the folic acid family have been synthesized, tested and discussed in the chemical and medical literature. The compounds have various activities at the enzymatic level; they inhibit such enzymes as dihydrofolate reductase, folate polyglutamate synthetase, glycinamide ribonucleotide formyltransferase and thymidylate synthase.
A problem inherent to pyrrolo[2,3-d]pyrimidine synthesis is preparing the reduced form; the 5,6-dihydro analogue. Using standard reduction methods, this reaction usually proceeds, if at all, with great difficulty. The pyrrolo[2,3-d]pyrimidine chromophore is found to be resistant to catalytic hydrogenation over palladium and platinum oxide catalysts. In addition, it is resistant to reduction by triethylsilane in trifloroacetic acid as well as reduction under conditions such as contact with hydrogen gas at 1250 psi in the presence of a 10% palladium-on-carbon catalyst.
Recently, a series of pyrrolopyrimidine derivatives has been disclosed as antifolate compounds having antineoplastic activity. See e.g., European Patent Publication 334 636, (Akimoto, et al.) and U.S. Pat. No. 4,997,838 (also, Akimoto, et ). Akimoto has shown a possible solution to this reduction problem by utilizing an isopropyloxymethyl protecting group at the 3-position and a benzyl group at the 7-position of the pyrrolopyrimidine. Although the presence of the protecting groups permits the preparation of 5,6-dihydropyrrolopyrimidines via catalytic hydrogenation, this synthesis is quite expansive, as the requisite protected substrate requires many steps to produce from commercially available materials.
The present invention provides novel intermediates for the preparation of 5,6-dihydropyrrolo[2,3-d]pyrimidine antifolate-type antimetabolites, and novel processes for the preparation of those intermediates. The processes are less laborious and thus provide an inexpensive means to prepare 5,6-dihydropyrrolo[2,3-d]pyrimidines.